Abstract 13304: Thrombin-activated Fibrinolysis Inhibitor in Chronic Thromboembolic Pulmonary Hypertension
Introduction: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) remains to be elucidated. In the present study, we examined whether fibrinolysis capacity is impaired in CTEPH patients with a special reference to thrombin-activated fibrinolysis inhibitor (TAFI) and if so, whether TAFI is also directly involved in the pathogenesis of CTEPH in mice and humans.
Methods and Results: We enrolled 68 consecutive patients undergoing right heart catheterization in our hospital, including those with CTEPH (n=27), those with pulmonary arterial hypertension (PAH, n=22) and controls (non-PH, n=19). Whole blood clot-lysis assay with monteplase (100 ng/ml) showed that thrombus reduction rate was significantly reduced in CTEPH compared with PAH or controls (58.1 vs. 73.5 and 75.1%, both P<0.01). Plasma clot-lysis assay showed that the clot lysis time tended to be prolonged in CTEPH compared with PAH or controls (894 vs. 652 and 720 sec, both P=0.07). Moreover, serum levels of TAFI were significantly higher in CTEPH than in PAH or controls (46.1 vs. 39.1 and 38.7 μg/ml, both P<0.05), which remained unchanged even after hemodynamic improvement by percutaneous transluminal pulmonary angioplasty (49.6 vs. 50.0 μg/ml, P=0.92). The levels of TAFI released from the platelets upon stimulation by thrombin (0.05 U/ml) were significantly higher in CTEPH than in PAH or non-PH (2.7 vs. 1.7 and 1.0 folds, both P<0.05). Additionally, thrombus reduction rate was significantly improved with a carboxypeptidase R (an inhibitor of activated TAFI) (62.0 vs. 73.4%, P<0.01) or prostaglandin E1 (an inhibitor of activation of platelets) (62.2 vs. 70.4%, P<0.01). Importantly, plasma levels of TAFI were correlated with thrombus reduction rate and improved thrombus reduction rate by an activated TAFI-inhibitor (both P<0.05). Finally, we newly developed TAFI-overexpressing mice (TAFI-Tg) and found that intravenous injection of thrombin (100 units/kg) caused accelerated thrombotic obstruction of the pulmonary artery in TAFI-Tg mice compared with littermate controls (5.4±1.2 vs. 1.8±0.6 vessels/lung fields) (n=9, P<0.05).
Conclusions: These results provide the first evidence that TAFI plays a crucial role in the pathogenesis of CTEPH.
Author Disclosures: N. Yaoita: None. K. Satoh: None. T. Satoh: None. K. Sugimura: None. S. Tatebe: None. S. Yamamoto: None. T. Aoki: None. M. Miura: None. H. Shimokawa: None.
- © 2015 by American Heart Association, Inc.